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Open AccessArticle

Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism

1
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Wagistr. 14, 8952 Schlieren, Switzerland
2
Department of Clinical Immunology, Jagiellonian University Medical College, 30-663 Cracow, Poland
3
Department for BioMedical Research, Department of Cardiology, University Hospital Bern, 3008 Bern, Switzerland
4
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK
5
Department of Public Health, University of Naples “Federico II”, 80131 Naples, Italy
6
InSphero, 8952 Schlieren, Switzerland
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(5), 1270; https://doi.org/10.3390/cells9051270
Received: 13 April 2020 / Revised: 10 May 2020 / Accepted: 19 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue 3D Stem Cell Culture)
Cardiac fibrosis represents a serious clinical problem. Development of novel treatment strategies is currently restricted by the lack of the relevant experimental models in a human genetic context. In this study, we fabricated self-aggregating, scaffold-free, 3D cardiac microtissues using human inducible pluripotent stem cell (iPSC)-derived cardiomyocytes and human cardiac fibroblasts. Fibrotic condition was obtained by treatment of cardiac microtissues with profibrotic cytokine transforming growth factor β1 (TGF-β1), preactivation of foetal cardiac fibroblasts with TGF-β1, or by the use of cardiac fibroblasts obtained from heart failure patients. In our model, TGF-β1 effectively induced profibrotic changes in cardiac fibroblasts and in cardiac microtissues. Fibrotic phenotype of cardiac microtissues was inhibited by treatment with TGF-β-receptor type 1 inhibitor SD208 in a dose-dependent manner. We observed that fibrotic cardiac microtissues substantially increased the spontaneous beating rate by shortening the relaxation phase and showed a lower contraction amplitude. Instead, no changes in action potential profile were detected. Furthermore, we demonstrated that contraction of human cardiac microtissues could be modulated by direct electrical stimulation or treatment with the β-adrenergic receptor agonist isoproterenol. However, in the absence of exogenous agonists, the β-adrenoreceptor blocker nadolol decreased beating rate of fibrotic cardiac microtissues by prolonging relaxation time. Thus, our data suggest that in fibrosis, activated cardiac fibroblasts could promote cardiac contraction rate by a direct stimulation of β-adrenoreceptor signalling. In conclusion, a model of fibrotic cardiac microtissues can be used as a high-throughput model for drug testing and to study cellular and molecular mechanisms of cardiac fibrosis. View Full-Text
Keywords: cardiac microtissues; iPSC-derived cardiomyocytes; cardiac fibroblasts; cardiac fibrosis; cardiac rhythm; TGF-β signalling; drug screening; in vitro model cardiac microtissues; iPSC-derived cardiomyocytes; cardiac fibroblasts; cardiac fibrosis; cardiac rhythm; TGF-β signalling; drug screening; in vitro model
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MDPI and ACS Style

Błyszczuk, P.; Zuppinger, C.; Costa, A.; Nurzynska, D.; Di Meglio, F.; Stellato, M.; Agarkova, I.; Smith, G.L.; Distler, O.; Kania, G. Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism. Cells 2020, 9, 1270. https://doi.org/10.3390/cells9051270

AMA Style

Błyszczuk P, Zuppinger C, Costa A, Nurzynska D, Di Meglio F, Stellato M, Agarkova I, Smith GL, Distler O, Kania G. Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism. Cells. 2020; 9(5):1270. https://doi.org/10.3390/cells9051270

Chicago/Turabian Style

Błyszczuk, Przemysław; Zuppinger, Christian; Costa, Ana; Nurzynska, Daria; Di Meglio, Franca; Stellato, Mara; Agarkova, Irina; Smith, Godfrey L.; Distler, Oliver; Kania, Gabriela. 2020. "Activated Cardiac Fibroblasts Control Contraction of Human Fibrotic Cardiac Microtissues by a β-Adrenoreceptor-Dependent Mechanism" Cells 9, no. 5: 1270. https://doi.org/10.3390/cells9051270

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